Marlène Rio
Necker-Enfants Malades Hospital
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Publication
Featured researches published by Marlène Rio.
Journal of Medical Genetics | 2004
Charles Shaw-Smith; Richard Redon; Lisa Rickman; Marlène Rio; Lionel Willatt; Heike Fiegler; Helen V. Firth; Damien Sanlaville; R Winter; Laurence Colleaux; M Bobrow; Nigel P. Carter
The underlying causes of learning disability and dysmorphic features in many patients remain unidentified despite extensive investigation. Routine karyotype analysis is not sensitive enough to detect subtle chromosome rearrangements (less than 5 Mb). The presence of subtle DNA copy number changes was investigated by array-CGH in 50 patients with learning disability and dysmorphism, employing a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Twelve copy number abnormalities were identified in 12 patients (24% of the total): seven deletions (six apparently de novo and one inherited from a phenotypically normal parent) and five duplications (one de novo and four inherited from phenotypically normal parents). Altered segments ranged in size from those involving a single clone to regions as large as 14 Mb. No recurrent deletion or duplication was identified within this cohort of patients. On the basis of these results, we anticipate that array-CGH will become a routine method of genome-wide screening for imbalanced rearrangements in children with learning disability.
Journal of Medical Genetics | 2007
Caroline Nava; Nadine Hanna; Caroline Michot; Sabrina Pereira; Nathalie Pouvreau; Tetsuya Niihori; Yoko Aoki; Yoichi Matsubara; Benoit Arveiler; Didier Lacombe; Eric Pasmant; Béatrice Parfait; Clarisse Baumann; Delphine Héron; Sabine Sigaudy; Annick Toutain; Marlène Rio; Alice Goldenberg; Bruno Leheup; Alain Verloes; Hélène Cavé
Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term “Costello syndrome” should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.
Epilepsia | 2008
Nadia Bahi-Buisson; Anna Kaminska; Nathalie Boddaert; Marlène Rio; Alexandra Afenjar; Marion Gérard; Fabienne Giuliano; Jacques Motte; Delphine Héron; Marie Ange N'Guyen Morel; Perrine Plouin; Christian Richelme; Vincent des Portes; Olivier Dulac; Christophe Philippe; Catherine Chiron; Rima Nabbout; Thierry Bienvenu
Mutations in the X‐linked cyclin‐dependent kinase‐like 5 (CDKL5) gene are responsible for a severe encephalopathy with early epilepsy. So far, the electroclinical phenotype remains largely unknown and no clear genotype–phenotype correlations have been established.
Journal of Medical Genetics | 2003
Marlène Rio; L Clech; Jeanne Amiel; L. Faivre; Stanislas Lyonnet; M. Le Merrer; Sylvie Odent; Didier Lacombe; Patrick Edery; Raja Brauner; O Raoul; Philippe Gosset; M Prieur; Michel Vekemans; Arnold Munnich; Laurence Colleaux; Valérie Cormier-Daire
Sotos syndrome is an overgrowth syndrome characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and typical facial features. Weaver syndrome is a closely related condition characterised by a distinctive craniofacial appearance, advanced carpal maturation, widened distal long bones, and camptodactyly. Haploinsufficiency of the NSD1 gene has recently been reported as the major cause of Sotos syndrome while point mutations accounted for a minority of cases. We looked for NSD1 deletions or mutations in 39 patients with childhood overgrowth. The series included typical Sotos patients (23/39), Sotos-like patients (lacking one major criteria, 10/39), and Weaver patients (6/39). We identified NSD1 deletions (6/33) and intragenic mutations (16/33) in Sotos syndrome patients. We also identified NSD1 intragenic mutations in 3/6 Weaver patients. We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series. Interestingly, mental retardation was consistently more severe in patients with NSD1 deletions. Macrocephaly and facial gestalt but not overgrowth and advanced bone age were consistently observed in Sotos syndrome patients. We suggest therefore considering macrocephaly and facial gestalt as mandatory criteria for the diagnosis of Sotos syndrome and overgrowth and advanced bone age as minor criteria.
Human Mutation | 2011
Louise Galmiche; Valérie Serre; Marine Beinat; Zahra Assouline; Anne-Sophie Lebre; Dominique Chretien; Patrick Nietschke; Vladimir Benes; Nathalie Boddaert; Daniel Sidi; Francis Brunelle; Marlène Rio; Arnold Munnich; Agnès Rötig
By combining exome sequencing in conjunction with genetic mapping, we have identified the first mutation in large mitochondrial ribosomal protein MRPL3 in a family of four sibs with hypertrophic cardiomyopathy, psychomotor retardation, and multiple respiratory chain deficiency. Affected sibs were compound heterozygotes for a missense MRPL3 mutation (P317R) and a large‐scale deletion, inherited from the mother and the father, respectively. These mutations were shown to alter ribosome assembly and cause a mitochondrial translation deficiency in cultured skin fibroblasts resulting in an abnormal assembly of several complexes of the respiratory chain. This observation gives support to the view that exome sequencing combined with genetic mapping is a powerful approach for the identification of new genes of mitochondrial disorders. Hum Mutat 32:1225–1231, 2011. ©2011 Wiley Periodicals, Inc.
American Journal of Human Genetics | 2004
Geneviève Baujat; Marlène Rio; Sylvie Rossignol; Damien Sanlaville; Stanislas Lyonnet; Martine Le Merrer; Arnold Munnich; Christine Gicquel; Valérie Cormier-Daire; Laurence Colleaux
Sotos syndrome is an overgrowth syndrome characterized by pre- and postnatal overgrowth, macrocephaly, advanced bone age, variable degrees of mental retardation, and typical facial features. Defects of the NSD1 gene account for >or=60% of cases of Sotos syndrome, whereas the disease-causing mechanism of other cases remains unknown. Beckwith-Wiedemann syndrome (BWS) is a distinct overgrowth condition characterized by macroglossia, abdominal-wall defects, visceromegaly, embryonic tumors, hemihyperplasia, ear anomalies, renal anomalies, and neonatal hypoglycemia. Deregulation of imprinted growth-regulatory genes within the 11p15 region is the major cause of BWS, whereas the molecular defect underlying a significant proportion of sporadic BWS cases remains unknown. Owing to clinical overlaps between the two syndromes, we investigated whether unexplained cases of Sotos syndrome could be related to 11p15 anomalies and, conversely, whether unexplained BWS cases could be related to NSD1 deletions or mutations. Two 11p15 anomalies were identified in a series of 20 patients with Sotos syndrome, and two NSD1 mutations were identified in a series of 52 patients with BWS. These results suggest that the two disorders may have more similarities than previously thought and that NSD1 could be involved in imprinting of the chromosome 11p15 region.
Human Mutation | 2009
Loïc de Pontual; Yves Mathieu; Christelle Golzio; Marlène Rio; Valérie Malan; Nathalie Boddaert; Christine Soufflet; Capucine Picard; Anne Durandy; Angus Dobbie; Delphine Héron; Bertrand Isidor; Jacques Motte; Ruth Newburry‐Ecob; Laurent Pasquier; Marc Tardieu; Géraldine Viot; Francis Jaubert; Arnold Munnich; Laurence Colleaux; Michel Vekemans; Heather Etchevers; Stanislas Lyonnet; Jeanne Amiel
Pitt‐Hopkins syndrome is a severe congenital encephalopathy recently ascribed to de novo heterozygous TCF4 gene mutations. We report a series of 13 novel PHS cases with a TCF4 mutation and show that EEG, brain magnetic resonance imagain (MRI), and immunological investigations provide valuable additional clues to the diagnosis. We confirm a mutational hot spot in the basic domain of the E‐protein. Functional studies illustrate that heterodimerisation of mutant TCF4 proteins with a tissue‐specific transcription factor is less effective than that homodimerisation in a luciferase reporter assay. We also show that the TCF4 expression pattern in human embryonic development is widespread but not ubiquitous. In summary, we further delineate an underdiagnosed mental retardation syndrome, highlighting TCF4 function during development and facilitating diagnosis within the first year of life. Hum Mutat 0, 1–8, 2009.
Human Mutation | 2008
Chantal Stheneur; Gwenaëlle Collod-Béroud; Laurence Faivre; Laurent Gouya; Gilles Sultan; Jean-Marie Le Parc; Bertrand Moura; David Attias; Christine Muti; Marc Sznajder; Mireille Claustres; Claudine Junien; Clarisse Baumann; Valérie Cormier-Daire; Marlène Rio; Stanislas Lyonnet; Henri Plauchu; Didier Lacombe; Bertrand Chevallier; Guillaume Jondeau; Catherine Boileau
TGFBR1 and TGFBR2 gene mutations have been associated with Marfan syndrome types 1 and 2, Loeys‐Dietz syndrome and isolated familial thoracic aortic aneurysms or dissection. In order to investigate the molecular and clinical spectrum of TGFBR2 mutations we screened the gene in 457 probands suspected of being affected with Marfan syndrome or related disorders that had been referred to our laboratory for molecular diagnosis. We identified and report 23 mutations and 20 polymorphisms. Subsequently, we screened the TGFBR1 gene in the first 74 patients for whom no defect had been found, and identified 6 novel mutations and 12 polymorphisms. Mutation‐carrying probands displayed at referral a large clinical spectrum ranging from the Loeys‐Dietz syndrome and neonatal Marfan syndrome to isolated aortic aneurysm. Furthermore, a TGFBR1 gene mutation was found in a Shprintzen‐Goldberg syndrome patient. Finally, we observed that the yield of mutation detection within the two genes was very low : 4.8% for classical MFS, 4.6% for incomplete MFS and 1% for TAAD in the TGFBR2 gene; 6.2%, 6.2% and 7% respectively in the TGFBR1 gene; in contrast to LDS, where the yield was exceptionally high (87.5%).
Science | 2011
Satoru Hashimoto; Sarah Boissel; Mohammed Zarhrate; Marlène Rio; Arnold Munnich; Jean-Marc Egly; Laurence Colleaux
A single missense mutation is linked to intellectual impairment. MED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.
Journal of Medical Genetics | 2002
Marlène Rio; Florence Molinari; Solange Heuertz; Catherine Ozilou; Philippe Gosset; O Raoul; Valérie Cormier-Daire; Jeanne Amiel; Stanislas Lyonnet; M. Le Merrer; Catherine Turleau; M-C de Blois; Marguerite Prieur; S. Romana; Michel Vekemans; Arnold Munnich; Laurence Colleaux
Recent studies have shown that cryptic unbalanced subtelomeric rearrangements contribute to a significant proportion of idiopathic syndromic mental retardation cases. Using a fluorescent genotyping based strategy, we found a 10% rate of cryptic subtelomeric rearrangements in a large series of 150 probands with severe idiopathic syndromic mental retardation and normal RHG-GTG banded karyotype. Fourteen children were found to carry deletions or duplications of one or more chromosome telomeres and two children had uniparental disomy. This study clearly shows that fluorescent genotyping is a sensitive and cost effective method that not only detects cryptic subtelomeric rearrangements but also provides a unique opportunity to detect uniparental disomies. We suggest giving consideration to systematic examination of subtelomeric regions in the diagnostic work up of patients with unexplained syndromic mental retardation.